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, Reinhard Dummer
Published: 1 November 2017
European Journal of Cancer, Volume 86, pp 101-105; https://doi.org/10.1016/j.ejca.2017.09.014

Abstract:
The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.
, , Corneel Coens, Marcel Den Dulk, , Damien Weber, Martin Spahn, Roberto Salgado, Bernd Kasper, , et al.
Published: 1 November 2017
European Journal of Cancer, Volume 86, pp 91-100; https://doi.org/10.1016/j.ejca.2017.07.039

Abstract:
Quality assurance (QA) programmes are one of the mainstays of clinical research and constitute the pillars on which European Organisation for Research Treatment of Cancer (EORTC) delivers multidisciplinary therapeutic progress. Changing practice treatments require solid evidence-based data, which can only be achieved if integral QA is part of the infrastructure sustaining research projects. Cancer treatment is a multimodality approach, which is often applied either in sequence and/or in combination. Each modality plays a key role in cancer control. The modalities by which QA is applied varies substantially within and across the disciplines. In addition, translational and diagnostic disciplines take an increasing role in the era of precision medicine. Building on the structuring effect of clinical research with fully integrated multidisciplinary QA programmes associated with the solutions addressing the chain of custody for biological material and data integrity as well as compliance ensure at the same time validity of clinical research output but also have a training effect on health care providers, who are more likely to apply such principles as routine. The principles of QA are therefore critical to be embedded in multidisciplinary infrastructure to guarantee therapeutic progress. These principles also provide the basis for the functioning of multidisciplinary tumour board. However, technical, operational and economic challenges which go with the implementation of such programmes require optimal know-how and the coordination of the multiple expertise and such efforts are best achieved through centralised infrastructure.
, Lorenza Marotti, Christopher D. Hart, Luigi Cataliotti, , , Robert E. Mansel, , Philip Poortmans, , et al.
Published: 1 November 2017
European Journal of Cancer, Volume 86, pp 59-81; https://doi.org/10.1016/j.ejca.2017.08.017

Abstract:
In 2010, EUSOMA published a position paper, describing a set of benchmark quality indicators (QIs) that could be adopted by breast centres to allow standardised auditing and quality assurance and to establish an agreed minimum standard of care. Towards the end of 2014, EUSOMA decided to update the paper on QIs to consider and incorporate new scientific knowledge in the field. Several new QIs have been included to address the need for improved follow-up care of patients following primary treatments. With regard to the management of elderly patients, considering the complexity, the expert group decided that, for some specific quality indicators, if centres fail to meet the minimum standard, older patients will be excluded from analysis, provided that reasons for non-adherence to the QI are specified in the clinical chart and are identified at the review of the clinical records. In this way, high standards are promoted, but centres are able to identify and account for the effect of non-standard treatment in the elderly. In the paper, there is no QI for outcome measurements, such as relapse rate or overall survival. However, it is hoped that this will be developed in time as the databases mature and user experience increases. All breast centres are required to record outcome data as accurately and comprehensively as possible to allow this to occur. In the paper, different initiatives undertaken at international and national level to audit quality of care through a set of QIs have been mentioned.
, S. Verma, L. Fallowfield, V. Müller, M. Lichinitser, , A. Sánchez Muñoz, Z. Machackova, S. Osborne, J. Gligorov
Published: 27 September 2017
European Journal of Cancer, Volume 86, pp 82-90; https://doi.org/10.1016/j.ejca.2017.08.019

The publisher has not yet granted permission to display this abstract.
, Chie Kudo-Saito, Reiko Muramatsu, Tomonobu Fujita, Miyuki Saito, Haruna Nagumo, Toshiharu Sakurai, Shinobu Noji, Emi Takahata, Tomonori Yaguchi, et al.
Published: 1 November 2017
European Journal of Cancer, Volume 86, pp 15-27; https://doi.org/10.1016/j.ejca.2017.08.026

Abstract:
We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8(+) T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8(+) T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8(+) T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8(+) T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8(+) T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8(+) FOXP3(+) T cells and immunodysfunctional CD8(+) GATA3(+) T cells were increased in adenocarcinoma of non-smokers. CD4(+) FOXP3(+) regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163(+) M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.
Mathilde Guerin, , , , Aurélie Autret, Jihane Pakradouni, Magali Provansal, Jacques Camerlo, , , et al.
Published: 1 November 2017
European Journal of Cancer, Volume 86, pp 28-36; https://doi.org/10.1016/j.ejca.2017.08.025

Abstract:
Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.NCT01589861.
Comment
Luigi Cataliotti, Lorenza Marotti, Marc Beishon, Alberto Costa, Susan Knox, Emiel Rutgers,
Published: 1 December 2017
European Journal of Cancer, Volume 87, pp 201-202; https://doi.org/10.1016/j.ejca.2017.06.044

, , K.I. Pritchard, D.M. Naimark
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 146-154; https://doi.org/10.1016/j.ejca.2017.08.018

Abstract:
The addition of palbociclib to letrozole is unlikely to be cost-effective for the treatment of ABC from a Canadian healthcare perspective with its current price. While ABC patients derive a meaningful clinical benefit from palbociclib, considerations should be given to increase the WTP threshold and reduce the drug pricing, to render this strategy more affordable.
, Lorena de la Pena, Valentina Nekljudova, Dimitrios Zardavas, , Carsten Denkert, Mahdi Rezai, Begoña Bermejo, Michael Untch, Soo Chin Lee, et al.
Published: 15 September 2017
European Journal of Cancer, Volume 85, pp 133-145; https://doi.org/10.1016/j.ejca.2017.08.020

The publisher has not yet granted permission to display this abstract.
, , Helle W. Hendel, Karin Dahlstroem, Krzysztof T. Drzewiecki, Tobias W. Klausen,
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 122-132; https://doi.org/10.1016/j.ejca.2017.07.052

Abstract:
To explore health-related quality of life (HRQoL) in recurrence-free melanoma patients, with a focus on the association between melanoma-related limb lymphoedema and HRQoL.HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the breast cancer module (EORTC QLQ-BR23) subscales body image and future perspective, the Functional Assessment for Cancer Therapy-General subscale social/family well-being and the Hospital Anxiety and Depression Scale. Data were analysed using linear and ordinal logistic regression adjusting for age and gender.A total of 431 melanoma patients who had undergone wide local excision and axillary or inguinal sentinel lymph node biopsy (SLNB) and/or complete lymph node dissection (CLND) participated. No patients had had recurrence of the disease or had received adjuvant radiotherapy. The HRQoL scores improved with time after surgery. Melanoma-related limb lymphoedema was present in 109 patients (25%). Patients with lymphoedema had significantly worse HRQoL scores in the EORTC QLQ-C30 subscales global health status/quality of life, role and social functioning, fatigue, pain and financial difficulties, as well as in the QLQ-BR23 body image subscale. No associations were found between the limb affected (upper or lower limb), clinical stage of lymphoedema, duration of lymphoedema or type of surgery (SLNB or CLND) and HRQoL. We found an interaction with age and gender in the associations between lymphoedema and HRQoL: younger patients and women with lymphoedema had worse social functioning and women had significantly more impaired body image.The negative impact of melanoma-related limb lymphoedema on HRQoL emphasises the importance of developing strategies for increasing awareness and improving prevention and treatment of lymphoedema.
E.A. Huis In 't Veld, D.J. Grünhagen, C. Verhoef, , , , F. van Coevorden, ,
Published: 15 September 2017
European Journal of Cancer, Volume 85, pp 114-121; https://doi.org/10.1016/j.ejca.2017.07.023

The publisher has not yet granted permission to display this abstract.
, O.S Hoekstra, F Homans, E Van Cutsem, A Maes, , , F Penninckx, L Filez, R.P Bleichrodt, et al.
Published: 1 May 2001
European Journal of Cancer, Volume 37, pp 862-869; https://doi.org/10.1016/s0959-8049(01)00049-1

Abstract:
The aim of the study was to evaluate the use of positron emission tomography with [ 18 F]-fluorodeoxyglucose (FDG-PET) in patients with unexplained rising carcinoembryonic antigen (CEA) in the postoperative surveillance of colorectal cancer. 50 consecutive patients with elevated CEA levels and a completely normal ( n =31) or equivocal ( n =19) conventional diagnostic work-up (CDW) were retrospectively selected. All PET images were reviewed with full knowledge of the CDW. The gold standard consisted of histology, or clinical follow-up of more than 1 year. Recurrent disease was established in 56 lesions in 43 patients. On a patient-based analysis, the sensitivity of FDG-PET was 34/43 (79%), and the positive predictive value 34/38 (89%). In 14/50 patients (28%), the FDG-PET findings led to a surgical resection with curative intent. On a lesion-based analysis, FDG-PET detected 42/56 lesions (sensitivity: 75%), the positive predictive value was 79% (42/53). These results demonstrate that FDG-PET can have a clear impact on patient management in patients with an unexplained elevation in CEA levels.
, L. Collette, , M. Brausi, W. Hoekstra, D.W. Newling, M. DeCoster
Published: 1 May 2001
European Journal of Cancer, Volume 37, pp 884-891; https://doi.org/10.1016/s0959-8049(01)00056-9

Abstract:
The aim of this study was to assess whether the quality of the surgical act could be an important prognostic factor for patients undergoing radical prostatectomy. This study also aims to investigate whether the surgical quality can be assessed by any means. Questionnaires were collected from 23 different institutes including 232 radical prostatectomies (RPr) performed for T1T2 prostate cancer. Blood loss, duration of surgery, margin status, postoperative prostate specific antigen (PSA) and urinary incontinence were analysed and correlated with the yearly number of RPr performed. The mean values obtained for each parameter were very different in the various centres. The outcome in terms of tumour control and incontinence could not be related to a higher or lower number of RPr performed. Quality control of RPr is feasible on the basis of an analysis of a few parameters, such as surgical margins, postoperative PSA and incontinence, that might recognise urologists that perform better or poorer than a proposed average.
V Vagunda, K Landys, J.-P Kankkunen, M Vagundova, , J Kovarik, J Hugosson
Published: 1 October 2001
European Journal of Cancer, Volume 37, pp 1847-1852; https://doi.org/10.1016/s0959-8049(01)00212-x

Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 106-113; https://doi.org/10.1016/j.ejca.2017.07.053

Abstract:
Advances in radiotherapy (RT) have allowed an increased proportion of lung cancer patients to be treated curatively. High doses delivered to critical thoracic organs can result in excess mortality with tolerance doses poorly defined. This work presents a novel method of identifying anatomical dose-sensitive regions within the thorax.A high-resolution, normal-tissue dosimetric analysis was performed to identify regions in the heart that correlate with poorer survival. A total of 1101 patients treated with curative-intent RT were selected and all computed tomography imaging and dose distributions were deformed to a reference. Mean dose distributions were created for patients who survived versus those who did not at a set time point. Statistical significance of dose differences was investigated with permutation testing. The dose received by the most statistically significant region of the thorax was collected in all patients and included in a multivariate survival analysis.The permutation testing showed a highly significant region across the base of the heart, where higher doses were associated with worse patient survival (p < 0.001). Cox-regression multivariate analysis showed region dose, tumour volume, performance status and nodal stage were significant factors associated with survival, whereas cardiac mean dose, V5 and V30 showed no significance. Survival curves, controlling for these factors, were plotted with patients receiving doses greater than 8.5 Gy to the identified region showing worse survival (log-rank p < 0.001, hazard ratio 1.2).The application of this novel methodology in lung cancer patients identifies the base of the heart as a dose-sensitive region for the first time.
Po-Lin Lin, Tzu-Chin Wu, De-Wei Wu, Lee Wang, Chi-Yi Chen,
Published: 8 September 2017
European Journal of Cancer, Volume 85, pp 95-105; https://doi.org/10.1016/j.ejca.2017.07.025

The publisher has not yet granted permission to display this abstract.
Published: 8 September 2017
European Journal of Cancer, Volume 85, pp 78-85; https://doi.org/10.1016/j.ejca.2017.07.050

Abstract:
Paediatric dose-finding studies are challenging to perform due to ethical reasons, the limited number of available patients and restricted number of blood samples. In certain cases, the adult pharmacokinetic (PK) exposure can be used as target for dose finding in paediatrics. The aim of this study was to investigate the performance of a paediatric phase I dose-finding clinical trial in silico. Using an adult pharmacokinetic model, clinical trial simulations were performed to determine the power of a proposed clinical trial design. Power was defined as the fraction of 1000 trials with an area under the plasma concentration–time curve at steady-state (AUC0-24,SS) within ±20% of the adult geometric mean AUC0-24,SS. Different scenarios were compared to optimise the design of the trial. To show the potential of this framework for similar compounds, the current simulation method was also evaluated with adult and paediatric data from literature on sunitinib. At the starting dose of 300 mg/m2, the power of the trial design was 66.9%. Power did not improve by dose escalation to 350 mg/m2 (65.3%). Power increased to 78.9% with inclusion of 10 patients per trial. Paediatric sunitinib PK data were adequately predicted from adult data with a mean prediction error of 1.80%. The performance of PK-based clinical trials in paediatrics can be predicted and optimised through PK modelling and simulation. Application of this approach enables clinical trials in paediatrics to be performed as efficiently as possible while protecting the child from unnecessary harm.
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 67-77; https://doi.org/10.1016/j.ejca.2017.08.014

Abstract:
Hodgkin lymphoma (HL) was one of the first few cancers to be cured first with radiotherapy alone and then with a combination of chemotherapy and radiotherapy. Around 80% of the patients with HL will be cured by first-line therapy. However, the ionising radiation not only produces cytotoxicity but also induces alterations in the microenvironment, and patients often struggle with the long-term consequences of these treatments, such as cardiovascular disorders, lung diseases and secondary malignancies. Hence, it is essential to improve treatments while avoiding delayed side-effects. Immunotherapy is a promising new treatment option for Hodgkin lymphoma, and anti- programmed death-1 (PD1) agents have produced striking results in patients with relapsed or refractory disease. The microenvironment of Hodgkin lymphoma appears to be unique in the field of human disease: the malignant Reed-Sternberg cells only constitute 1% of the cells in the lymphoma, but they are surrounded by an extensive immune infiltrate. Reed-Sternberg cells exhibit 9p24.1/PD-L1/PD-L2 copy number alterations and genetic rearrangements associated with programmed cell death ligand 1/ ligand 2 (PD-L1/2) overexpression, together with major histocompatibility complex-I (MHC-I) and major histocompatibility complex-II (MHC-II) downregulation (which may facilitate the tumour's immune evasion). Although HL may be a situation in which defective immune surveillance is restored by anti-PD1 therapy, it challenges our current explanation of how anti-PD1 agents work because MHC-I expression is required for CD8-T-cell-mediated tumour antigen recognition. Here, we review recent attempts to understand the defects in immune recognition in HL and to design an optimal evidence-based treatment for combination with anti-PD1.
, , , E. Sportoletti-Baduel, E. Manubens, A. Barreiro, V. Caliendo, M. Chavez-Bourgeois, , P. Cassoni, et al.
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 59-66; https://doi.org/10.1016/j.ejca.2017.07.051

Abstract:
Different protocols have been used to follow up melanoma patients in stage I-II. However, there is no consensus on the complementary tests that should be requested or the appropriate intervals between visits. Our aim is to compare an ultrasound-based follow-up with a clinical follow-up.Analysis of two prospectively collected cohorts of melanoma patients in stage IB-IIA from two tertiary referral centres in Barcelona (clinical-based follow-up [C-FU]) and Turin (ultrasound-based follow-up [US-FU]). Kaplan-Meier curves were used to evaluate distant metastases-free survival (DMFS), disease-free interval (DFI), nodal metastases-free survival (NMFS) and melanoma-specific survival (MSS).A total of 1149 patients in the American Joint Committee on Cancer stage IB and IIA were included in this study, of which 554 subjects (48%) were enrolled for a C-FU, and 595 patients (52%) received a protocolised US-FU. The median age was 53.8 years (interquartile range [IQR] 41.5-65.2) with a median follow-up time of 4.14 years (IQR 1.2-7.6). During follow-up, 69 patients (12.5%) in C-FU and 72 patients (12.1%) in US-FU developed disease progression. Median time to relapse for the first metastatic site was 2.11 years (IQR 1.14-4.04) for skin metastases, 1.32 (IQR 0.57-3.29) for lymph node metastases and 2.84 (IQR 1.32-4.60) for distant metastases. The pattern of progression and the total proportion of metastases were not significantly different (P = .44) in the two centres. No difference in DFI, DMFS, NMFS and MSS was found between the two cohorts.Ultrasound-based follow-up does not increase the survival of melanoma patients in stage IB-IIA.
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 49-58; https://doi.org/10.1016/j.ejca.2017.08.013

Abstract:
High-dose methotrexate (HDMTX)-based regimens are widely used in osteosarcoma. However, mandatory in-patient treatment with complex pharmacokinetic monitoring requirement precludes its use, especially in resource-constrained settings of low- and middle-income countries (LMICs).All treatment naive consecutive patients of osteosarcoma were prospectively treated on a novel institutional regimen (named OGS-12) comprising of eight sequential doublets of the following drugs: doxorubicin, cisplatin and ifosfamide in four courses each, given in the neoadjuvant and adjuvant settings. Data were prospectively collected on baseline characteristics, histological response to neoadjuvant chemotherapy (NACT), toxicity, event-free survival (EFS) and overall survival (OS).Between 2011 and 2014, 317 treatment naive patients with extremity osteosarcoma were seen, of whom 237 (75%) were non-metastatic. Majority had high tumour burden, with mean tumour size of 10.45 cm, high serum lactate dehydrogenase (LDH) and serum alkaline phosphatase (SAP) in 71% and 88% respectively. A significant number (34%) were nutritionally challenged. Two-hundred ten of 237 patients were analysable for histological response of which 58% had good response (viable cells ≤10%). At the median follow-up of 34.31 (2-60) months, in intention-to-treat (ITT) analysis, the 5-year EFS and OS were 56% and 75% respectively; the same were 60% and 80% in per-protocol analysis. There was febrile neutropenia (FN) in 56%, grade 3/4 thrombocytopaenia in 22% and anaemia in 47% with two chemotoxic deaths. Ten percent of the patients had grade 3/4 diarrhoea and stomatitis and one patient developed grade 4 acute kidney injury requiring dialysis. Baseline SAP (per-protocol) for EFS and performance status (ITT) for OS were found to be independent variables. Histological response was an independent predictor for EFS and OS in both the analyses.In treatment naive patients with non-metastatic osteosarcoma, OGS-12 protocol, a dose-dense, non-HDMTX-based, novel, economic and easy to administer regimen produces comparable outcomes to international standards, with acceptable toxicity and is worthy of wider clinical application.
, , , Laurence Digue, , Anne Gimbert, Emmanuelle Chauzit, Rémi Sitta, , Julien Asselineau, et al.
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 39-48; https://doi.org/10.1016/j.ejca.2017.07.031

Abstract:
Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.
, M. Tomatis, L. Marotti, , R.E. Mansel, M. Rosselli del Turco, D. Casella, L.G. Bassani, M. Danei, A. Denk, et al.
Published: 4 September 2017
European Journal of Cancer, Volume 85, pp 15-22; https://doi.org/10.1016/j.ejca.2017.07.040

The publisher has not yet granted permission to display this abstract.
Johanna Daroles, , Voichita Suciu, , ,
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 23-30; https://doi.org/10.1016/j.ejca.2017.08.002

Abstract:
A short-term radiologic follow-up after a benign breast biopsy or fine needle aspiration (FNA) is recommended in many guidelines. However, the current trend is to reduce imaging investigations, radiation dose and costs. The objectives of this study were to evaluate the cancer detection rate at short-term follow-up and to estimate its cost.We retrospectively assessed all consecutive patients referred to our 'one-stop' breast unit between 2004 and 2012, with a benign histological or cytological result and at least one short-term follow-up within 3-12 months after the initial diagnosis. We evaluated the number of cancers detected, as well as the mean cost to detect each cancer and per patient.About 1366 patients were eligible for this study. Ten patients were diagnosed with cancers (0.73%) at short-term follow-up; six of 10 were low-grade tumours or ductal carcinoma in situ. The cost for detecting one cancer was 19,043€, with mean cost per patient of 139€.The cancer detection rate at short-term follow-up after benign biopsy or FNA was low and was similar to that of most national screening programs. The cost of cancer detection appeared high, considering that most cancers were indolent. This suggests that radiologic follow-up could reasonably be carried out at a later point in time.
, P.S. Hall, , J.A. Dunn, C.C. McConkey, J.K. Rahman, C. McCabe,
Published: 1 November 2017
European Journal of Cancer, Volume 85, pp 6-14; https://doi.org/10.1016/j.ejca.2017.07.054

Abstract:
A recent large United Kingdom (UK) clinical trial demonstrated that positron-emission tomography-computed tomography (PET-CT)-guided administration of neck dissection (ND) in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned ND (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT-guided management from a UK secondary care perspective.Initial 6-month cost and health outcomes were derived from trial data; subsequent incidence of recurrence and mortality was simulated using a de novo Markov model. Health benefit was measured in quality-adjusted life years (QALYs) and costs reported in 2015 British pounds. Model parameters were derived from trial data and published literature. Sensitivity analyses were conducted to assess the impact of uncertainty and broader National Health Service (NHS) and personal social services (PSS) costs on the results.PET-CT management produced an average per-person lifetime cost saving of £1485 and an additional 0.13 QALYs. At a £20,000 willingness-to-pay per additional QALY threshold, there was a 75% probability that PET-CT was cost-effective, and the results remained cost-effective over the majority of sensitivity analyses. When adopting a broader NHS and PSS perspective, PET-CT management produced an average saving of £700 and had an 81% probability of being cost-effective.This analysis indicates that PET-CT-guided management is cost-effective in the long-term and supports the case for wide-scale adoption.
, , , Nicole Scobie, Delphine Heenen,
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 149-158; https://doi.org/10.1016/j.ejca.2017.07.021

Abstract:
Oncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation.Data on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website.Over 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high-risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma.The Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer.
, , , , Heiddis B. Valdimarsdottir, , , , Eleonora B.L. van Dorst, Hans W.H.M. van der Putten, et al.
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 159-167; https://doi.org/10.1016/j.ejca.2017.07.018

Abstract:
There has been some doubts raised in earlier studies about the efficacy of hormone replacement therapy (HRT) in reducing endocrine and sexual problems in women who have undergone a risk-reducing salpingo-oophorectomy (RRSO).In this prospective, observational study, we recruited 178 premenopausal women with a high risk for ovarian cancer. Fifty-seven women opted for RRSO and 121 for gynaecological screening (GS). Women completed questionnaires before surgery (T1) and 3 (T2) and 9 (T3) months post surgery, or at equivalent time points for the GS-group. Menopausal symptoms were assessed with the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) and sexual functioning with the Sexual Activity Questionnaire (SAQ). Groups were compared using repeated measures mixed effect models for continuous variables, and generalised estimating equations for longitudinal ordered categorical data.Twenty-seven women who underwent RRSO used HRT after surgery (HRT-users) and 30 did not (HRT-non-users). There were no significant group differences at baseline on the outcome variables. Compared to the HRT-users, the HRT-non-users exhibited a significant increase in overall endocrine symptoms (p = 0.001, effect size (ES) = -0.40 and p < 0.001, ES = -0.59 at T1 and T2, respectively), and in sexual discomfort (p < 0.001, ES = 0.74 and p < 0.001, ES = 1.17). The effect size provides an indication of the magnitude of the observed group differences. An effect size of 0.50 or greater is generally considered to be clinically relevant. No significant differences over time were observed between the HRT-users and the GS-group on any of the outcomes.Our results suggest that HRT use in the first year after RRSO has beneficial effects in terms of minimising endocrine symptoms and sexual symptoms in premenopausal women who have undergone RRSO.
Xuchen Zong, , Paul E. Grundy, Salaheddin M. Mahmud, ,
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 173-183; https://doi.org/10.1016/j.ejca.2017.06.035

Abstract:
Few studies in North America have quantified the risks of second malignant neoplasms (SMNs) among survivors of childhood non-central nervous system (non-CNS) embryonal tumours due to their rarity. We aimed to investigate these risks by combining population-based data from the United States of America and Canada. We evaluated patients with childhood non-CNS embryonal tumours reported to the Surveillance Epidemiology and End Results program and eight Canadian cancer registries from 1969 to 2010. Standardised incidence ratio (SIR) and cumulative incidence of SMNs were calculated. Subgroup analyses were conducted by the type of first primary cancer, age at first primary diagnosis and follow-up duration. Of the 13,107 survivors, 190 SMNs were reported over 134,548 person-years of follow-up. The SIR for all SMNs combined was 6.4 (95% confidence interval [CI]: 5.5-7.4). Most site-specific SIRs were significantly increased, ranging from 36 (95% CI: 26-49) for bone and joint cancer to 3.1 (95% CI: 1.5-5.2) for brain tumour. The risk for second malignancies declined as the time elapsed from the first primary diagnosis and was less prominent for patients first diagnosed at age 1-4 years. Notably, rhabdomyosarcoma survivors had a higher risk for SMNs than those with other first primaries. The overall cumulative incidence of SMNs was 1.0% at 10 years, increasing to 2.2% at 20 years and 4.1% at 30 years. Survivors with childhood non-CNS embryonal tumours faced an increased risk for SMNs compared to the general population. The risk variations observed in different patient categories may help target prevention strategies in high-risk subgroups.
Tao Jiang, , Xuefei Li, , , Mary O'Brien
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 168-172; https://doi.org/10.1016/j.ejca.2017.07.036

Abstract:
Accumulating evidence suggest that patients with advanced non-small-cell lung cancer (NSCLC) and specific genomic alterations including epidermal growth factor receptor and microtubule-associated protein-like 4 anaplastic lymphoma kinase could significantly benefit from molecular-targeted therapies compared with chemotherapy. Recently, immunotherapy based on programmed cell death 1 (PD-1) and its ligand (PD-L1) blockade prolong survival in patients with advanced NSCLC, especially in those patients with positive expression of PD-L1 and when used in the first-line setting. Therefore, the diagnosis, clinical staging and molecular genotyping must be quick and efficient so that we can make a timely and precise decision for treatment strategy. In our department, it takes a median 4 working days (range 3-6) for a new patient from initial respiratory consultation to treatment decision, whereas in many countries, 14 workdays is considered a reasonable timeline. In this article, we will provide detailed information on the diagnostic pathway for a new patient suspected of having lung cancer to the final treatment decisions in our department.
Fang Li, Tengjiao Zhu, Baoshan Cao, ,
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 184-192; https://doi.org/10.1016/j.ejca.2017.07.037

Abstract:
Apatinib significantly potentiated the antitumour effect of gefitinib in NSCLC with T790M-related EGFR-TKI resistance both in vivo and vitro. EGFR-TKI rechallenge with apatinib might represent a new option for NSCLC with T790M or unknown resistance mechanism.
, , , Tracy Lively, Shakun Malik, , , Jeffrey A. Moscow, , Tawnya McKee, et al.
Published: 30 August 2017
European Journal of Cancer, Volume 84, pp 325-334; https://doi.org/10.1016/j.ejca.2017.07.028

The publisher has not yet granted permission to display this abstract.
H. De La Pena, , C. Glicksman, , , Z. Traill, C. Verrill, M. Sullivan, J. Redgwell, E. Bataillard, et al.
Published: 31 August 2017
European Journal of Cancer, Volume 84, pp 354-359; https://doi.org/10.1016/j.ejca.2017.07.005

Abstract:
Following radical orchidectomy for testicular cancer, most patients undergo protocolled surveillance to detect tumour recurrences rather than receive adjuvant chemotherapy. Current United Kingdom national and most international guidelines recommend that patients require a chest x-ray (CXR) and serum tumour markers at each follow-up visit as well as regular CT scans; there is however, variation among cancer centres with follow-up protocols. Seminomas often do not cause tumour marker elevation; therefore, CT scans are the main diagnostic tool for detecting relapse. For non-seminomatous tumours, serum beta-HCG (HCG) and AFP levels are a very sensitive harbinger of relapse, but this only occurs in 50% of patients [1], and therefore, imaging remains as important. CXRs are meant to aid in the detection of lung recurrences and before the introduction of modern cross-sectional imaging in the early 1980s, CXRs would have been the only method of identifying lung metastasis. We examined the Thames Valley and Mount Vernon Cancer Centre databases to evaluate the role of CXRs in the 21st century for the follow-up of men with stage I testicular cancer between 2003 and 2015 to assess its value in diagnosing relapsed germ cell tumours. From a total of 1447 patients, we identified 159 relapses. All relapses were detected either by rising tumour markers or planned follow-up CT scans. Not a single relapse was identified on CXR. We conclude that with timely and appropriate modern cross-sectional imaging and tumour marker assays, the CXR no longer has any value in the routine surveillance of stage I testicular cancer and should be removed from follow-up guidelines and clinical practice. Omitting routine CXR from follow-up schedules will reduce anxiety as well as time that patients spend at hospitals and result in significant cost savings.
, David Brandao, , Etienne Rouleau, Olivier Caron, Emmanuelle Despras, Yolla El-Dakdouki, , , , et al.
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 290-303; https://doi.org/10.1016/j.ejca.2017.07.026

Abstract:
Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon (POLE) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE-mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine.
, Kristina Magnusson, , , , , , , Jan Frisell, Irma Fredriksson
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 278-289; https://doi.org/10.1016/j.ejca.2017.07.044

Abstract:
Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis.Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged ≥40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins.Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR- tumours (hazard ratio [HR] 0.47 [0.24-0.92]). Age <40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22-4.50]). Young women with luminal B PR- tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A (HR 6.21 [2.17-17.6]).The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR+ tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours.
Tobin Strom, Louis B. Harrison, Anna R. Giuliano, Michael J. Schell, Steven A. Eschrich, , William Fulp, Ram Thapa, Domenico Coppola, Sungjune Kim, et al.
Published: 29 August 2017
European Journal of Cancer, Volume 84, pp 304-314; https://doi.org/10.1016/j.ejca.2017.08.001

The publisher has not yet granted permission to display this abstract.
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 315-324; https://doi.org/10.1016/j.ejca.2017.07.032

Abstract:
There is variation in margin policy for breast conserving therapy (BCT) in the UK and Ireland. In response to the Society of Surgical Oncology and American Society for Radiation Oncology (SSO-ASTRO) margin consensus ('no ink on tumour' for invasive and 2 mm for ductal carcinoma in situ [DCIS]) and the Association of Breast Surgery (ABS) consensus (1 mm for invasive and DCIS), we report on current margin practice and unit infrastructure in the UK and Ireland and describe how these factors impact on re-excision rates.A trainee collaborative-led multicentre prospective study was conducted in the UK and Ireland between 1st February and 31st May 2016. Data were collected on consecutive BCT patients and on local infrastructure and policies.A total of 79 sites participated in the data collection (75% screening units; average 372 cancers annually, range 70-900). For DCIS, 53.2% of units accept 1 mm and 38% accept 2-mm margins. For invasive disease 77.2% accept 1 mm and 13.9% accept 'no ink on tumour'. A total of 2858 patients underwent BCT with a mean re-excision rate of 17.2% across units (range 0-41%). The re-excision rate would be reduced to 15% if all units applied SSO-ASTRO guidelines and to 14.8% if all units followed ABS guidelines. Of those who required re-operation, 65% had disease present at margin.There continues to be large variation in margin policy and re-excision rates across units. Altering margin policies to follow either SSO-ASTRO or ABS guidelines would result in a modest reduction in the national re-excision rate. Most re-excisions are for involved margins rather than close margins.
, , E.J. Th. Rutgers, C.H. Smorenburg, Th. van Dalen, S. Siesling
Published: 1 October 2017
European Journal of Cancer, Volume 84, pp 270-277; https://doi.org/10.1016/j.ejca.2017.07.042

Abstract:
In Dutch guidelines, gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is uncertain based on traditional prognostic factors alone. Aim of the present study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk).Clinical low- and high-risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011 and 2014 were selected from the Netherlands Cancer Registry. Influence of GEP use and GEP test result on CT administration was assessed with logistic regression.Overall, 26,425 patients were identified; 4.8% of patients with clinical low risk (444/9354), 7.5% of the patients with a clinical high risk (1281/17,071) received a GEP. GEP use was associated with significantly increased odds of CT administration in clinical low-risk patients (OR = 2.12 95% CI: 1.44-3.11). In clinical high-risk patients, GEP use was associated with a decreased frequency of CT administration (OR = 0.55, 95% CI: 0.48-0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively.GEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test result was limited.
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